1. Field of Invention
The present invention mainly provides a gall bladder imaging agent and its preparation method.
2. Related Art
Tc-99m-di-isopropyl iminodiacetic acid (DISIDA) is a gall bladder imaging agent in clinical use, which is an analog of bilirubin and has a similar metabolic pathway in human body. Tc-99m-DISIDA can accumulate at a gall bladder and is mostly used to estimate whether a cystic duct is unobstructed to diagnose an infant with biliary atresia in an early period. However, Tc-99m-DISIDA is not suitable for patients with liver dysfunctions. Patients with liver dysfunctions absorb Tc-99m DISIDA drugs very slowly and drugs cannot accumulate at the gall bladder easily, so it is very difficult to observe whether bile transportation is unobstructed with this agent. Patients with liver dysfunctions need to seek other methods.
Asialoglycoprotein receptor (ASGPR) is a liver specific receptor and has specific binding to glycopeptides or glycoproteins with galactose (Gal) or acetylgalactosamine (GalNAc) at an end. These glycopeptides and glycoproteins enter a liver cell through endocytosis of a liver receptor and eventually exits through a bile duct, and accordingly are theoretically applicable for scanning and imaging of gall bladders, and are used to observe the presence of symptoms of biliary atresia. It has been found through earlier researches in our laboratory that ASGPR disappears only when all liver cells have turned into liver cancer cells. Otherwise, as long as there are normal liver cells, ASGPR is present to absorb glycopeptides or glycoproteins with Gal or GalNAc at an end. Therefore, it is technically feasible for an ASGPR biological imaging marker (that is, glycopeptides or glycoproteins with Gal or GalNAc at an end) to serve as a gall bladder imaging agent.
Conventional technetium-99m-diethylenetriamine pentaacetic acid-galactosyl-albumin (Tc-99m-DTPA-GSA) can be used in liver imaging. Albumin is used as a backbone, on which an unpredictable number of galactosyls and DTPA are connected. The number of connected DTPA is different by batch as the fabrication process cannot be controlled. Therefore, the labelling amount of technetium-99m also changes with the DTPA, and accordingly the specific radioactivity is very different in each time of preparation. Also, the metabolic rate of Tc-99m-DTPA-GSA in the liver is very slow and it is difficult to observe the absorption of the gall bladder, so that Tc-99m-DTPA-GSA is not suitable for use as a gall bladder imaging agent.
Tyrosine-glutamyl-glutamic acid (YEE) and tyrosine-aspartyl-aspartic acid (YDD) are first proposed by Lee et al. (1983). Tyrosine-glutamyl-glutamyl-glutamic acid (YEEE) is an improved invention by Chen et al. (ROC Patent TW1240002, 2000). The binding force between double-chain galactose amino peptide proposed by Lee et al. in 1983 and a liver cell is 1000 times as large as that of single-chain galactose amino peptide. The binding force between triple-chain galactose amino peptide and a liver cell is 106 times as large as that of sing-chain galactose amino peptide. Our laboratory has synthesized DTPA-hexa-lactose with a single lysine derivative earlier, which has very high specific radioactivity with the In-111 label and has a very desirable effect of accumulation at the liver in animal experiments. However, our animal experiments have shown that In-111-DTPA-hexa-lactose stays at the liver very stably for at least half an hour, and it is actually not easy to observe changes of absorption of the gall bladder in the entire imaging process. Therefore, In-111-DTPA-hexa-lactose is suitable for use in remaining liver function test or measurement of remaining liver after liver resection, but is not very suitable for use as a gall bladder imaging agent.